The present invention relates to substituted 4(5)-(1-indanyl and 1-indanylmethyl and 1-indanylmethylen)imidazoles and 4(5)-[1-(1,2,3,4-tetrahydronaphthyl and 1,2,3,4-tetrahydronaphthylmethyl and 1,2,3,4-tetrahydronaphthylmethylen]imidazoles and to their isomers, pharmaceutically acceptable salts and esters. It also relates to their preparation, use and to pharmaceutical compositions containing them.
The compounds of the invention have affinity for alpha2 receptors most of them being very selective alpha2 agonists. Accordingly, they are useful in the treatment of hypertension, glaucoma, migraine, diarrhea, ischemia, addiction to chemical substances (such as tobacco and narcotics) and different neurological, musculoskeletal, psychiatric and cognition disorders as well as sedative and analgesic agents, nasal decongestants, and adjuncts to anaesthesia.
Gregory G. B., et al describe in J. Org. Chem. (1990), 55, 1479-1483 a new synthesis step for 1-phenylalkyl-1-(4-imidazolyl)-1,2,3,4-tetrahydronaphthalene derivatives which are useful as nonpeptide antagonists of the angiotensin II receptor.
The imidazole derivatives of the invention are either compounds of formula I 
n is 0 or 1
R1 is hydrogen or C1-C4-alkyl
R2 is hydrogen or R2 and R3 together form a double bond
R3 is hydrogen or C1-C4-alkyl or R2 and R3 together form a double bond
R4 is hydrogen, C1-C4-alkyl, hydroxy or C1-C4-alkoxy
R5 is hydrogen or C1-C4-alkyl or R4 and R5 together with the carbon atom to which they are attached form a carbonyl group
R6, R7 and R8 are each the same or different and are independently hydrogen, C1-C4-alkyl or C2-C4-alkenyl, C3-C7-cycloalkyl, hydroxy, C1-C4-alkoxy, C1-C4-hydroxyalkyl, thiol, C1-4-alkylthio, C1-4-alkylthiol, halogen, trifluoromethyl, nitro or optionally substituted amino
X is xe2x80x94CHR9xe2x80x94(CHR10)mxe2x80x94
m is 0 or 1
and R9 and R10 are each the same or different and are independently hydrogen or C1-C4-alkyl;
or a pharmaceutically acceptable ester or salt thereof.
The terms as employed herein have the following meanings: A halogen is e.g. chlorine, bromine or fluorine, preferably it is chlorine or fluorine. The C1-C4-alkyl, C1-C4-alkoxy and C2-C4-alkenyl etc. groups may be branched or straight chain groups. C3-C7-Cycloalkyl is a saturated cyclic hydrocarbon group having preferably 3 to 5 carbon atoms. Optionally substituted amino is an amino group which is unsubstituted or substituted with a C1-C4-alkyl group.
When m=n=0 
R3 is preferably hydrogen,
R4 is preferably hydrogen, hydroxy or C1-C4-alkoxy, such as ethoxy,
R5 is preferably hydrogen, or R4 and R5 form, together with the carbon atom to which they are attached, a carbonyl group.
R6 is preferably hydrogen, C1-C4-alkyl or C1-C4-alkoxy, such as methyl, ethyl, t-butyl, methoxy or hydroxy. For example, R6 may be C1-C4-alkyl at position 4, 5 or 6, a C1-C4-alkoxy at position 5, 6 or 7, or hydroxy at position 5 or position 7.
More preferably R6 is hydrogen, 4-methyl, 6-methyl or 7-methoxy.
R7 is preferably at position 5, 6 or 7.
R7 is preferably hydrogen or C1-C4-alkyl, such as, for example methyl or t-butyl. For example R7 may be a C1-C4-alkyl at position 5, 6 or 7, such as 5-methyl, 7-methyl or 6-t-butyl.
More preferably R7 is hydrogen.
R8 is preferably at position 6 or 7.
R8 is preferably hydrogen, hydroxy or C1-C4-alkoxy, such as methoxy. For example, R8 may be a C1-C4-alkoxy at position 6, such as 6-methoxy, or 6-hydroxy or 7-hydroxy.
R9 is preferably hydrogen or methyl.
When n=1 and m=0
R1 is preferably hydrogen or methyl.
R2, R3, R4, R5 and R9 are preferably hydrogen,
R6 is preferably hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy, such as, for example, methyl or t-butyl, methoxy or hydroxy. R6 is preferably at position 4, 5 or 6. For example, R6 may be a C1-C4-alkyl at position 4, 5 or 6, such as 4- or 5-methyl or 5-t-butyl or a C1-C4-alkoxy at position 5 or 6, such as 5- or 6-methoxy, or 4-, 5- or 6-hydroxy. R6 may be halogen at position 5 or 6, such as 5- or 6-fluoro.
More preferably R6 is 4-, 5- or 6-hydroxy.
R7 is preferably at position 5, 6 or 7.
R7 is preferably hydrogen, C1-C4-alkyl, C1-C4-alkoxy or hydroxyl. For example, R7 may be C1-C4-alkyl at position 5, 6 or 7, such as 5- or 7-methyl or 5- or 6-t-butyl or C1-C4-alkoxy at position 6, such as 6-methoxy, or 6-hydroxy.
More preferably R7 is hydrogen or 6-hydroxy or 6-t-butyl.
R8 is preferably at position 6 or 7.
R8 is preferably hydrogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, such as methyl or methoxy, for example C1-C4-alkyl at position 7, such as 7-methyl or 7-t-butyl or C1-C4-alkoxy at position 6, such as 6-methoxy or 6-hydroxy.
When n=m=1 
R1, R2, R3, R5, R8, R9 and R10 are preferably hydrogen.
R4 is preferably hydrogen or C1-C4-alkyl, such as, for example, methyl.
R6 is preferably at position 5, 6 or 7.
R6 is preferably hydrogen, C1-C4-alkoxy or hydroxy, for example methoxy. For example, R6 may be 5-, 6- or 7-methoxy, or 6- or 7-hydroxy.
R7 is preferably hydrogen or C1-C4-alkyl, such as, for example, t-butyl.
When n=0 and m=1
R3, R4, R5, R7, R8, R9 and R10 are preferably hydrogen.
R6 is preferably hydrogen or halogeN, for example chlorine. R6 may be a halogen at position 5, such as, for example 5-chloro.
The invention includes within its scope all the possible isomers and stereoisomers, in particular Z and E (cis and trans isomers) and enantiomers.
The compounds of the formula (I) form acid addition salts with both organic and inorganic acids. Typical acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates. Furthermore, compounds wherein one or more of R4 to R8 is a hydroxy group form esters and salts with alkali metals and alkaline earth metals. Typical esters include the lower alkyl esters, such as the methyl, ethyl and propyl esters.
The compounds of the invention may be prepared using the following methods. (It is to be noted that in the formulae below, when the imidazole group is protected, the protecting group Rxe2x80x2 (benzyl or trityl) may be attached to either of the two nitrogen atoms of the imidazole ring. Accordingly, the use of 1-benzyl-5-imidazolecarbaldehyde as starting material leads to 1.5 substituted derivatives whereas when trityl is used the substitution is mainly 1.4.)
Synthesis of 4(5)-(1-indanyl)imidazoles and the corresponding 4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles
Method a
Compounds of formula I wherein n=0 and m=0 or 1 may be prepared by an acid catalyzed cyclization of protected or unprotected 4(5)-(1-hydroxy-3-phenylpropyl or 1-hydroxy4-phenylbutyl)imidazoles of formulae II and IIxe2x80x2, respectively.
Accordingly, the 4(5)-(1-indanyl)imidazoles may be prepared by cyclization of the compound of formula II 
wherein R3 to R9 are as defined above and Rxe2x80x2 is a protecting group, in the presence of an acid to form the compounds of formula III 
wherein the substituents are as defined above, and removing the protecting group Rxe2x80x2 to form the compounds of formula Ia 
The corresponding 4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles may be prepared by cyclization of the compound of IIxe2x80x2
wherein R3 to R10 are as defined above I and Rxe2x80x2 is a protecting group in the presence of an acid to form the compounds of formula IIIxe2x80x2
wherein the substituents are as defined above, and removing the protecting group Rxe2x80x2 to form the compounds of formula Iaxe2x80x2
wherein the substituents are as defined above.
The protecting group Rxe2x80x2 may be, for example, benzyl or trityl. When Rxe2x80x2 is trityl it may be removed using an acid and, when it is benzyl, by catalytic hydrogenation. The acid used in the cyclization reaction may be, for example, polyphosphoric acid (PPA) or methanesulfonic acid.
The starting materials (compounds of the formulae II and IIxe2x80x2, respectively) may be synthesized using different methods. One of them is to prepare xcex1,xcex2-unsaturated ketones through an aldol condensation by allowing an imidazolyl alkyl ketone to react with an appropriately substituted benzaldehyde in the presence of a base: 
The accompanying reduction of carbonyl and the following catalytic hydrogenation produces saturated alcohols used in the cyclization. The reduction of the carbonyl group may be performed for example with sodium borohydride. If the imidazole moiety has been substituted with the benzyl group it may also be removed by catalytic hydrogenation.
To accomplish substitution at the position 1 of the indane or 1,2,3,4-tetrahydronaphthalene ring it is possible to carry out an 1,2-addition reaction of the intermediate ketone with a nucleophile before the hydrogenation. This is conveniently perfomed through the Grignard reaction which is carried out by adding to the reaction mixture an alkyl magnesium halide, e.g. bromide, made from alkyl halide and magnesium: 
Another useful method to produce appropriate alcohols needed as starting materials in the cyclization is the use of the Grignard reaction in the preparation of 4(5)-(1-hydroxy-phenylalkyl)imidazoles. Here the 4(5)-imidazole carbaldehyde or ketone is allowed to react with a Grignard reagent, prepared from appropriately substituted phenylalkyl halide and magnesium: 
Method b
To obtain substitution at the position 3 of the indane group the following procedure may be used: An intermediate of formula Ib, which is also an active compound wherein R4 and R5 together form a carbonyl group, is prepared. 
There are different methods for the preparation of this intermediate.
Firstly, it may be prepared using an acid catalyzed cyclization of 1-aryl-3-[4(5)-imidazolyl]-xcex1,xcex2-unsaturated-1-propanones: 
The xcex1,xcex2-unsaturated ketone used as the starting material in the above reaction may be prepared by a base catalyzed aldol condensation from substituted or unsubstituted 4(5)-imidazole carbaldehyde and from appropriately substituted phenyl alkyl ketone.
Secondly, it may be prepared through the condensation of benzyl protected urocanic acid with an appropriately substituted benzene: 
The benzyl protection is abolished by hydrogenation as described earlier.
The ketone group may be then further modified using different methods. It may be reduced to the corresponding alcohol with sodium borohydride or by catalytic hydrogenation, whereafter the alcohol may be hydrogenated: 
It is also possible to modify the ketone group using Grignard reaction: 
These compounds may be further transformed to compounds of formula I wherein n=m=0 and R4 is an alkyl and R5 is hydrogen by catalytic hydrogenation as described above.
The compounds of formula Ib wherein R4 is alkoxy and R5 is hydrogen may be prepared from the corresponding alcohol in concentrated hydrochloric acid.
Method c
A further method to synthesize the 4(5)-(1-indanyl)imidazoles of the formula I is to use the lithiated imidazole in an aromatic electrophilic substitution reaction with an 1-indanone (imidazole being bis-protected according to the method described by Kudzma et al. in Synthesis, (1991), p. 1021). The protection may be removed by acid treatment, which induces the simultaneous loss of water. The double bond is reduced by catalytic hydrogenation as described above. 
Syntehesis of 4(5)-(indan-1-ylmethyl)imidazoles and 4(5)-(indan-1-ylmethylen)imidazoles and the corresponding tetrahydronaphthyl derivatives
Method d
The preparation of 4(5)(indan-1-ylmethyl and indan-1-ylmethylen)imidazole and the corresponding tetrahydronaphthyl skeleton may be accomplished using the so called McMurry reaction, in which an imidazole carbaldehyde or ketone reacts with an 1-indanone. The reaction is catalyzed by low valence titanium. The condensation may be followed by the hydrogenation of the double bond and simultaneous elimination of the protecting group in the imidazole ring. 
The compounds of the invention may be administered enterally, topically or parenterally. Parenteral administration is used, for example, when the compounds are given as sedative or anxiolytic agents in connection to different clinical operations and to cause analgesia or to potentiate anesthesia.
The compounds of the invention may be formulated alone or together with another active ingredient and/or a pharmaceutically acceptable diluent or carrier to different pharmaceutical unit dosage forms i.e. tablets, capsules, solutions, emulsions and powders etc. using conventional techniques. The pharmaceutical carriers employed are selected with the planned manner of administration in mind. Thus, solid carriers may include lactose, sucrose, gelatin and agar, while liquid carriers typically include waters syrup, peanut oil and olive oil. The amount of the active ingredient varies from 0.01 to 75 weight-% depending on the type of the dosage form.
The appropriate oral dosage for the compounds of the invention depends on several factors such as the compound to be administrated, the species, age and the sex of the subject to be treated, the condition to be treated and on the method of administration. Accordingly, the dosage for parenteral administration is typically from 0.5 xcexcg/kg to 10 mg/kg per day and that for oral administration is from 5 xcexcg/kg to 100 mg/kg for an adult male.
The invention also provides a compound of the invention or an ester or salt thereof for use in a method of treatment of human or animal body.
The present invention further provides a compound of the invention or an ester or salt thereof for use in the treatment of hypertension, glaucoma, chronic and acute pain, migraine, diarrhea, common cold, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety and different neurological, musculoskeletal, psychiatric and cognition disorders or as an adjunct to anesthesia.
The invention also provides the use of a compound of the invention or an ester or salt thereof in the manufacture of a medicament for the treatment of hypertension, glaucoma, chronic and acute pain, migraine, diarrhea, common cold, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety and different neurological, musculoskeletal, psychiatric and cognition disorders or as an adjunct to anesthesia.
The invention further relates to a method for the treatment of hypertension, glaucoma, chronic and acute pain, migraine, diarrhea, common cold, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety and different neurological, musculoskeletal, psychiatric and cognition disorders by administering to a subject in need of such treatment an effective amount of the compound of the invention or a pharmaceutically acceptable ester or salt thereof.
1. Alpha2 agonism in rat vas deferens model
Alpha2 agonism was determined by means of isolated, electrically stimulated prostatic portions of rat vas deferens preparation (Virtanen et al. Arch. Int. Pharmacodyn et Ther. 297 (1989), pp. 190-204). In this model, an alpha2 agonist is able to inhibit electrically induced muscular contractions by activating the presynaptic alpha2 adrenoceptors and thus diminishing the secretion on the motor transmitter. The known alpha2 agonist dexmedetomidine was used as reference substance. Results are shown in Table 1, where the alpha2 agonist effect is presented as the pD2-value (negative logarithm of the molar concentration of the compound producing 50 percent of maximal inhibition).
The following compounds were tested:
1 4-(4-Methylindan-1-yl)-1H-imidazole hydrochloride
2 3-(1H-Imidazol-4-ylmethyl)-indan-5-ol hydrochloride
3 4-[1-(Indan-1-yl)-ethyl]-1H-imidazole hydrochloride
4 8-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-ol hydrochloride
5 dexmedetomidine (reference compound)
2. Binding assays
Affinities for xcex12-adrenoceptors and xcex11-adrenoceptors were estimated by determining the displacement of 1 nM 3H-RX821002 (xcex12) or 0.1 nM 3H-prazosin (xcex11) from xcex1-adrenoceptors in rat neocortical membranes. For this purpose membranes were incubated with different concentrations of test compounds spanning a concentration range of five orders of magnitude. Nonspecific binding was defined with 10 xcexcM phentolamine. Membranes were used at a protein concentration of 2 mg/ml in a total volume of 250 xcexcl. The incubation buffer consisted of 50 mM TRIS-HCl, pH 7.7. After a 30 min incubation at 25xc2x0 C. samples were filtered through glass fibre filter and filters were washed three times with 4 ml icecold wash buffer consisting of 10 mM TRIS-HCl, pH 7.7. Filters were then dried, impregnated with a scintillation cocktail and counted in a scintillation counter. Experimental data was analyzed using the commercial nonlinear least squares computer program LIGAND.
Each compound was tested in at least three independent experiments for its affinity on rat neocortical xcex12- or xcex11-adrenoceptors. The results are shown in Table 2.
The following examples illustrate how compounds of the invention may be prepared.